Epidemiología de la Tuberculosis miliar y extrapulmonar

8/17/2015 Epidemiology and pathology of extrapulmonary and miliary tuberculosis

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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorJohn Bernardo, MD

Section EditorC Fordham von Reyn, MD

Deputy EditorElinor L Baron, MD, DTMH

Epidemiology and pathology of extrapulmonary and miliary tuberculosis

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Feb 07, 2014.

INTRODUCTION — Miliary tuberculosis (TB) refers to clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis. The

term “miliary” was coined in 1700 by John Jacobus Manget, who likened the appearance of the involved lung with its surface covered with firm small white

nodules to numerous millet seeds (picture 1). Miliary TB can arise as a result of progressive primary infection or via reactivation of a latent focus with

subsequent spread. Originally a pathologic and then a radiographic description, the term miliary TB is now used to denote all forms of progressive, widely

disseminated hematogenous TB, even if the classical pathologic or radiologic findings are absent.

Tuberculosis may be classified according to site of disease as pulmonary or extrapulmonary; miliary disease has been classified as both an

extrapulmonary and a pulmonary form of TB.

The epidemiology and pathology of miliary TB will be reviewed here. The clinical manifestations, diagnosis, treatment, and prevention of miliary TB are

discussed separately. (See "Clinical manifestations, diagnosis, and treatment of extrapulmonary and miliary tuberculosis".)

EPIDEMIOLOGY — The epidemiology of tuberculosis (TB) and the miliary form of the disease have been altered by the introduction of effective

chemotherapy, the HIV epidemic, and immigration patterns. Of 9945 incident cases reported in the United States in 2012, extrapulmonary TB with no

demonstrated pulmonary involvement accounted for approximately 21 percent of cases (2100 cases). In an additional 1016 cases (10 percent), disease in

pulmonary and extrapulmonary sites was reported; these included 349 cases (3.5 percent of total) with miliary disease [1]. This reflected a minor increase

from 1.8 percent of reported cases in 2006. Worldwide, estimates of its incidence are hampered largely by incomplete reporting and imprecise diagnostic

criteria; it is estimated that miliary TB accounts for 1 to 2 percent of all cases of TB in immunocompetent persons [2].

The epidemiology of miliary disease varies in different case series:

®

®

Prior to the availability of antituberculous therapy, 20 percent of TB autopsy cases at Boston City Hospital had evidence of miliary disease [3]. By the

1970s, with the availability of antituberculous therapy, the incidence had fallen to 0.7 percent [4].

●

Data from the Centers for Disease Control and Prevention (CDC) in the early 1980s (after the availability of antituberculous therapy but prior to the

HIV epidemic) reported 1.3 percent of TB cases had evidence of miliary disease [5].

●

In the midst of the HIV epidemic during the mid 1980s, the percentage of miliary TB was higher among HIV-infected patients than HIV-uninfected

patients (38 versus 8 percent) [6,7]. Risk for developing miliary TB appeared to be highest among patients with the lowest CD4 counts [8].

●

In a public health clinic in Ireland in the 1990s, miliary disease accounted for 4 percent of TB cases [9].●

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The HIV epidemic has played a significant role in increasing the prevalence of miliary TB. Between 1999 and 2006 in England and Wales, an almost

fivefold increase in the number of miliary cases was observed (38 to 180 cases); HIV coinfection was most strongly associated with miliary disease [10].

Other factors, such as the emergence of drug-resistant or multidrug-resistant strains, have also contributed [11].

Risk factors — Risk factors for the development of miliary TB include age and underlying medical conditions, especially HIV infection. However, a

significant percentage of cases described in the literature have no demonstrable high-risk condition for dissemination; miliary TB should never be excluded

as a clinical diagnosis because an underlying medical illness is absent.

Age — Infants and young children are highly susceptible to miliary TB, presumably due to their relatively immature immune systems [12-16]. In a

study from Puerto Rico, miliary disease or meningitis occurred more frequently among children <6 years than among children >7 years of age (1 versus

0.4 percent, respectively) [13]. In another series from South Africa, miliary TB accounted for more hospital admissions among children than adults (8

versus 1 percent); 52 percent of cases occurred in children <1 year of age [14].

Miliary TB has been described more frequently among elderly adults in the post-antibiotic era than the pre-antibiotic era; this group is likely at increased

risk due to relative waning of cellular immunity [4]. In addition, the rise of HIV has led to increased prevalence of miliary TB among young adults [17].

Medical conditions — The percentage of patients with miliary TB and some identifiable underlying medical condition in various studies ranged from 38

to 70 percent. The most common conditions include [18-24]:

Weight loss and/or malnutrition are important components of a number of these conditions but have not been addressed separately [18-22].

Other factors — Men outnumber women in most series of miliary TB (table 1); it is uncertain whether this reflects a greater prevalence of TB among

men. It is also uncertain whether African-Americans are more likely to progress from infection to disseminated disease, since control for the relative

contributions of socioeconomic factors, such as living conditions, nutrition, access to care, and comorbidities, is needed for proper data interpretation [25].

PATHOLOGY

Mechanisms of disease — Miliary tuberculosis (TB) can arise as a result of progressive primary infection or via reactivation of a latent focus with

subsequent spread. Rarely, iatrogenic infection can occur.

Progressive primary disease — After establishing a focus of infection in the lung, bacilli can disseminate via the lymphatics and hematogenously

(algorithm 1). There is a predilection for spread to the most vascular organs, such as the liver, spleen, bone marrow, and brain. These distant foci usually

Alcohol abuse●

Malignancy●

Human immunodeficiency virus (HIV) infection●

Corticosteroids or other iatrogenic immunosuppression (eg, TNF-alpha blocking agents)●

Connective tissue disease (with or without iatrogenic immunosuppression)●

Renal failure●

Diabetes●

Pregnancy●


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heal by granulomatous encapsulation over weeks to months, containing viable organisms. Failure of these foci to heal early following primary infection

leads to progressive primary disease. Many adult patients with progressive TB have underlying medical or iatrogenic conditions that impair the

development of effective cell mediated immunity intended to contain the primary infection.

Reactivation of a latent focus — Miliary TB may result from reactivation of a latent focus of infection with subsequent erosion into adjoining

lymphatics or blood vessels, leading to dissemination of viable organisms. Reactivation may occur at any time after the primary infection; commonly it

occurs years or decades later, in association with demonstrable waning of specific immune responses, or in the presence of a high risk condition

associated with progressive TB. (See 'Risk factors' above.)

Iatrogenic infection — Rarely, miliary TB may occur as a result of iatrogenic exposure. Disseminated TB has been reported after extracorporeal

shock wave lithotripsy [26,27], urethral catheterization [28], and cardiac valve homograft placement [29]. TB has also been transmitted by solid organ

transplantation [30,31].

Clinicopathologic patterns of disease — Classically, the clinical and pathologic patterns of miliary TB have been divided into three groups: acute miliary

TB, late generalized TB, and anergic (nonreactive) TB. These terms can be confusing because there is considerable overlap among the categories and the

terminology is no longer frequently used. Acute miliary TB is primarily a clinical term; this entity can be seen in the immediate post-primary period or in

immunocompromised children or adults. It is usually observed within the first two to six months following exposure, although progression may be more

rapid in neonates and children under the age of one year [32]. During one TB outbreak in an HIV housing facility in San Francisco, 11 of 30 HIV-infected

residents (37 percent) who were exposed to an infectious pulmonary case of TB developed TB disease within 106 days; in one HIV-infected contact, TB

was diagnosed within four weeks of exposure [33].

Late generalized TB is primarily a pathologic term, referring to hematogenous dissemination without evidence of an active primary focus. Patients with an

acute miliary presentation may in fact have evidence of late generalized disease on histopathology.

Acute miliary tuberculosis — Acute (generalized) miliary TB has a relatively rapid clinical course [3,34]. Prior to the availability of effective

chemotherapy for TB, most cases of acute miliary TB resulted from progressive primary disease. The pathologic hallmark of acute miliary TB is a

caseating granulomatous reaction (picture 2), with a smaller number of organisms than other forms of miliary disease [3,34].

Late generalized tuberculosis — Late generalized TB refers hematogenous spread that occurs after the primary or post-primary period. In one

autopsy series of 100 patients with late generalized TB from 1937 to 1959, patients had relatively chronic, clinically nonspecific presentations [35]. In this

study, late generalized TB was frequently associated with chronic pulmonary TB. Since the availability of chemotherapy for TB, however, foci responsible

for hematogenous spread are extrapulmonary in some cases and are thus more difficult to detect.

A subset of late generalized TB is labeled cryptic miliary TB. This term refers to patients in whom the illness is even more indolent and who may

demonstrate an attenuated histologic response [35,36].

Anergic tuberculosis — Anergic TB is defined histologically by the absence of granulomata. In some cases, microabscesses containing large

numbers of bacilli with a predominantly neutrophilic response are observed, although, in general, anergic TB is relatively difficult to establish based on

histology [37]. Tissue stains and cultures are generally more sensitive diagnostic tools.

Anergic (nonreactive) TB is a relatively uncommon form of miliary disease. The clinical spectrum ranges from overwhelming sepsis to nonspecific or















typhoidal presentations. Most of the described cases are older patients with presumed reactivation TB. Granulomas in immunocompromised patients with

TB may share similar characteristics [38].

Host and pathogen factors — The major determinants of TB dissemination include mycobacterial virulence factors [39] and host immune defenses. The

high susceptibility of infants to miliary TB has led some investigators to speculate that the developing immune system may lack critical elements for

initiating protective responses to M. tuberculosis [15,16]. After initial infection, the development of specific cell-mediated immunity appears to be critical in

limiting disseminated disease. Cytokines, including TNF-alpha, interleukin (IL)-12 and interferon gamma, are essential for granuloma development and

protective immunity to M. tuberculosis [40,41]. (See "Natural history, microbiology, and pathogenesis of tuberculosis" and "Immunology of tuberculosis".)

SUMMARY

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REFERENCES

Miliary tuberculosis (TB) refers to clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis that affects multiple

organs and systems. Miliary TB can arise as a result of progressive primary infection or via reactivation of a previously contained latent focus with

subsequent spread. Miliary TB accounts for approximately 3 percent of incident cases in the United States, with increased representation among

infants and young children and in individuals with concomitant immunosuppression. Extrapulmonary TB accounts for approximately 20 percent of

cases. (See 'Introduction' above and 'Epidemiology' above.)

●

Risk factors for the development of miliary TB include extremes of age and underlying medical conditions. Infants are highly susceptible to miliary

TB, presumably due to their relatively immature immune systems. Elderly adults are also at increased risk for miliary TB due to relative waning of

cellular immunity. Underlying medical conditions conferring increased risk for miliary TB include alcohol abuse, malignancy, HIV infection,

immunosuppression (including chronic corticosteroid use and TNF-alpha inhibitors), connective tissue disease, renal failure, diabetes, and

pregnancy. (See 'Risk factors' above.)

●

After establishing a primary focus of infection in the lung, tuberculous bacilli can disseminate via the lymphatics and hematogenously to the most

vascular organs, such as the liver, spleen, bone marrow, and brain. These distant foci usually heal by granulomatous encapsulation over weeks to

months. Failure of these foci to heal within the first six months after primary infection leads to progressive primary disease. Healed, latent foci can

reactivate at any time after the primary infection; most commonly, reactivation occurs years or decades after primary infection, in association with

waning of cellular immune responses or other risk factors. (See 'Mechanisms of disease' above.)

●

Acute (generalized) miliary TB has a relatively rapid clinical course. This entity can be seen in the immediate post-primary period or as a result of

reactivation of a chronic focus; prior to the availability of anti-TB chemotherapy, most cases resulted from progressive primary disease. The

pathologic hallmark of acute miliary TB is a caseating granulomatous reaction. (See 'Acute miliary tuberculosis' above.)

●

Late generalized TB refers hematogenous spread that occurs after the primary or post-primary period. Prior to the availability of effective TB

chemotherapy, late generalized TB was frequently associated with chronic pulmonary TB. (See 'Late generalized tuberculosis' above.)

●

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1. http://www.cdc.gov/tb/statistics/reports/2012/pdf/report2012.pdf (Accessed on January 30, 2014).

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9. O'Reilly P, McDonnell T. The spectrum of mycobacterial disease in a Dublin teaching hospital. Ir Med J 1999; 92:299.

10. Kruijshaar ME, Abubakar I. Increase in extrapulmonary tuberculosis in England and Wales 1999-2006. Thorax 2009; 64:1090.

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13. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974;99:131.

14. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991; 10:832.

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24. Maartens G, Willcox PA, Benatar SR. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Am J


























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26. Morano Amado LE, Amador Barciela L, Rodriguez Fernandez A, et al. Extracorporeal shock wave lithotripsy complicated with miliary tuberculosis. JUrol 1993; 149:1532.

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29. Anyanwu CH, Nassau E, Yacoub M. Miliary tuberculosis following homograft valve replacement. Thorax 1976; 31:101.

30. Qunibi WY, al-Sibai MB, Taher S, et al. Mycobacterial infection after renal transplantation--report of 14 cases and review of the literature. Q J Med1990; 77:1039.

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32. PERRY TL. Natural history and pathogenesis of miliary and meningeal tuberculosis in children; analysis of 163 cases. Pediatrics 1950; 5:988.

33. Daley CL, Small PM, Schecter GF, et al. An outbreak of tuberculosis with accelerated progression among persons infected with the humanimmunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med 1992; 326:231.

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GRAPHICS

Comparative size of millet seeds

Millet seeds from which the name miliary tuberculosis derives

compared to the size of a dime (right) and a centimeter scale (left).

These correspond to the approximate size of miliary lesions seen on

chest radiograph.

Courtesy of Nesli Basgoz, MD.

Graphic 76174 Version 1.0



Major clinical series of miliary tuberculosis

First

author,

year

Years

includedLocation Inclusion criteria

# of

patients

Percent

male

Race,

percent

Maartens,

1990

1978 to

1987

Groote Schuur

Hospital (community-

based teaching

hospital in South

Africa)

Miliary pattern on CXR plus MTB on culture

from any site; or biopsy or autopsy

evidence of miliary organ involvement with

TB

109 51 African,

45,

mixed,

49,

white, 6

Kim, 1990 1975 to

1988

Duke University

Medical Center and

Durham VA Hospital

Durham, North

Carolina

Discharge diagnosis of disseminated or

miliary TB

38 50 African-

American,

50*

Gelb,

1973

1960 to

1970

UCLA Hospital Los

Angeles, California

Miliary pattern on CXR and one or more: 109 59 African-

American,

811. MTB on culture

2. Biopsy or autopsy showing caseating

granulomas with AFB

3. Clinical presentation and response

consistent with TB

Munt,

1971

1954 to

1970

Sanitorium drawing

from eastern part of

North Carolina

"Acute, diffuse pulmonary and extra-

pulmonary dissemination of TB, usually

associated with a miliary pattern on CXR,

with either MTB by culture or response to

TB therapy"

69 65 African-

American,

87

Proudfoot,

1969

1954 to

1967

Edinburgh, Scotland "Adults diagnosed in Edinburgh as having

disseminated TB"

40 40 Non-

British,

<1

Biehl,

1957

1951 to

1956

Cincinatti General

(city teaching

hospital Cincinatti,

Bacteriologic or pathologic diagnosis of

miliary tuberculosis or probable diagnosis

with response to therapy

68 69 African-

American,

23



Ohio)

CXR: chest radiograph; MTB: Mycobacterium tuberculosis; TB: tuberculosis; AFB: acid-fast bacilli.

* Excluding VA population.




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Pathogenesis of tuberculosis and miliary tuberculosis

TB: tuberculosis.





Miliary tuberculosis of the spleen

Miliary tuberculosis of the spleen. The cut surface shows numerous

gray-white granulomas.

Reproduced from: Kumar V, Abbas AK, Fausto N, Mitchell RN. Robbins Basic

Pathology, 8th ed, Saunders Elsevier, Philadelphia 2007. Illustration used

with the permission of Elsevier Inc. All rights reserved.




Disclosures: John Bernardo, MD Nothing to disclose. C Fordham von Reyn, MD Nothing to disclose. Elinor L Baron, MD, DTMH Nothingto disclose.

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Epidemiología de la Tuberculosis miliar y extrapulmonar